Paraneoplastic cerebellar degeneration. -...

Paraneoplastic cerebellar degeneration

I A clinical analysis of 55 anti-Yo antibody-positive patients

K Peterson MD MK Rosenblum MD H Kotanides MS and JB Posner MD

Article abstract-We reviewed the clinical findings in 55 patients with cerebellar degeneration associated with the anti-Yo antibody (an anti-Purkinje cell antibody identified in this study by histochemistry and Western blot) The patients were all women 26 to 85 years old Fifty-two of them proved to have malignancies almost exclusively breast or gynecologic cancers and usually confined to the involved organs and local lymph nodes One woman had adenocarcinoma of the lung and in three no malignancy has yet been identified In 34 of 52 patients with cancer the neurologic syndrome preceded the diagnosis of cancer and in many led to that diagnosis Patients subacutely developed a pancerebellar disorder that was substantially disabling in most with 37 of 48 assessable patients being unable to walk or sit unassisted Laboratory evaluation revealed lymphocytic pleocytosis in 35 patients with eventual cerebellar atrophy on imaging studies in seventeen The disabling neurologic syndrome generally did not respond to treatment but the cancer was often successfully treated The presence of the anti-Yo antibody in patients with cerebellar symptoms warrants an aggressive approach to diagnosis and treatment of the underlying cancer as many are curable at the time neurologic symptoms develop

NEUROLOGY 1992 421931-1937

Paraneoplastic cerebellar degeneration (PCD) is a clinical syndrome in which cerebellar dysfunction is associated with identifiable or occult cancer but without direct involvement of the nervous system by the cancer Typically the disorder evolves subacutely causes severe pancerebellar dysfunction and is associated with extensive Purkinje cell loss sometimes accompanied by meningeal and deep cerebellar nuclear inflammatory infiltrates1-3 Up until 1982 Henson and Urich3 were able to identify only 50 pathologically proven cases Even with recent renewed interest in the disorder the num- ber of patients reported in the literature is about two h ~ n d r e d ~ Although the disorder is rare Henson and Urich3 estimate that at least 50 of middle-aged patients who present with a subacutely developing pancerebellar disorder prove within a few years to have cancer

It is increasingly apparent that PCD despite its rarity subdivides into several disorders that can be distinguished clinically and immunologically and that differ in their prognoses and in the types of associated malignancies The clinical findings in 55

patients with one of these disorders PCD associated with a particular autoantibody designated ldquoanti- YOrdquo are described in this paper The two papers thatfollow (pages 1938 and 1944) describe PCD associated with Hodgkinrsquos disease and an unusual variant of PCD associated with small-cell lung cancer (SCLC) in which the majority of patients also have the Lambert-Eaton myasthenic syndrome A fourth disorder in which PCD may be the present- ing symptom of a more widespread encephalomyeli- tis associated with SCLC and an antinuclear antibody called ldquoanti-Hursquo is detailed e l ~ e w h e r e ~ ~ Recognizing the specific variant of PCD on clinical grounds and with immunologic testing often allows the physician to better predict the clinical course and direct the search for an underlying occult malignancy

Methods Patients The medical records of all anti- Yo-positive patients (defined by immunohistochemistry and immunoblotting) identified in our laboratory were reviewed Eighteen of these patients had been reported previ~usly~ Since only 10 of the 55 patients were exam-

From the Departments of Neurology Drs Peterson and Posner) and Pathology (Dr Rosenblum) and the George C Cotzias Laboratory of Neuro- Oncology (H Kotanides and Dr Posner) Memorial Sloan-Kettering Cancer Center and the Department of Neurology and Neuroscience (Drs Peterson and Posner) Cornell University Medical College New York NY Supported in part by NIH Grant NS26064

Presented in part at the 43rd annual meeting of the American Academy of Neurology Boston MA April 1991

Received January 17 1992 Accepted for publication in final form March 24 1992

Address correspondence and reprint requests to Dr Jerome B Posner Department of Neurology Memorial Sloan-Kettering Cancer Center 1275 York Avenue New York NY 10021 Dr Petersonrsquos current address is Department of Neurology University of Minnesota Medical School Minneapolis MN

October 1992 NEUROLOGY 42 1931

ined by one or more of the authors referring physicians sending sera andlor CSF for antibody testing provided the neurologic and oncologic profiles Telephone calls to the physicians most recently caring for the patients provided follow-up as of December 1991 Microscopic slides and blocks of the cerebellum obtained at autopsy in three patients and tumor tissue in seven patients were studied directly by us

Serum and CSF database Approximately 2000 sera andor CSF samples have been examined in our laboratory for the presence of anticerebellar antibodies These samples were sent from throughout the United States and many other countries by physicians suspecting the diagnosis of a neurologic paraneoplastic syndrome Some patients had known cancers whereas others did not All samples were s tudied by immunofluorescence or immunoperoxidase histochemistry and by Western blotting against Purkinje cell extracts A search of the data- bank also identified all patients in 1989 and 1990 with cerebellar syndromes with or without cancer and all patients with ovarian or breast cancer with or without cerebellar syndromes

Immunologic techniques Immunohistochemistry and Western blott ing techniques against Purkinje cell extracts as well as the CDR 62 fusion protein that corre- sponds to the 62 kd antigen to which the anti-Yo antibody binds have been described extensively in previous publications from this l a b ~ r a t o r y ~ - ~

Results Immunologic findings Serum or CSF from 55 patients was positive for the anti-Yo antibody as determined by immunohistochemistry and Western blotting In 41 of 41 patients tested sera also reacted positively against the Yo fusion pro- tein14

Several patients who had atypical histochemical staining andor atypical immunoblotting were excluded Excluded patients included one whose serum was positive by histochemistry but reacted on Western blotting against Purkinje cell extracts with a band of 68 kd (but not 34 kd ) and was negative against the Yo fusion protein Three patients had atypical Purkinje cell cytoplasmic staining and were negative on immunoblotting Two patients with PCD showed neuronal nuclear staining and a band at 35 to 40 kd on Western blot (typical of the anti-Hu antibody) but were negative when tested against the Yo fusion protein and one other with atypical nuclear staining was negative with both immunoblotting techniques

Thirteen patients with Hodgkins disease and PCD 45 patients with breast cancer and 24 with ovarian cancer with or without cerebellar syndromes 325 patients with cerebellar syndromes with or without cancer and 50 normal controls (blood bank donors) were also negative by both histochemistry and immunoblotting

Clinical results The 55 patients with the typical anti-Yo antibody presented a stereotypic clinical syndrome All patients were women 26 to 85 years old

Tumors Fifty-two of the patients currently have histologically proven malignancies The most common tumor ovarian was found in 26 of 55 patients

1932 NEUROLOGY 42 October 1992

13 had breast cancer and seven had other gynecologic malignancies (four endometrial two fallopian tube and one mesovarium) One patient had both breast and fallopian tube cancers One patient had an adenocarcinoma of the lung and is without known gynecologic malignancy

There were six patients with adenocarcinoma of unknown primary Three of these presented with axillary nodes likely representing breast cancer although no primary was found in the breast One patient with adenocarcinoma of unknown primary had had resection 2 years previously of an ovarian mass that had shown benign pathology at autopsy this patient was found to have had a periaortic node pathologically suggestive of ovarian cancer and had staining for CA 125 antigen which is associated with ovarian cancers One patient presented with carcinoma in an inguinal lymph node One other patient had a poorly differentiated adenocarcinoma in an abdominal lymph node compatible with ovarian cancer but no ovarian tumor was found At autopsy 3 years later she was found to have a hepatoma but no adenocarcinoma the origi- nal primary was not found

Three patients had no tumor identified One of these patients had resection of an ovarian mass with benign histology (ovarian cystadenoma) she died 24 months after the onset of her neurologic syndrome and no cancer was found at autopsy Two patients are still living up to 24 months after the onset of their neurologic disorder and have so far shown no evidence of malignancy despite serial physical and radiologic examinations

In 34 of 52 patients with known cancer the neurologic syndrome preceded the diagnosis of malignancy by up to 15 months and in many of the cases prompted a search for the underlying cancer Of these 34 patients 16 had ovarian cancer notably four had microscopic disease not found by routine diagnostic testing and detected only at laparotomy However one patient with a negative mammogram and normal pelvic examination underwent laparoscopy with ovarian biopsy and then hys- terectomy and bilateral salpingo-oophorectomy without a malignancy being found Four months after the initial normal mammogram a breast abnormality was detected and biopsy revealed an intraductal carcinoma

Most patients with known cancer had limited oncologic disease at the time of onset of neurologic symptoms with only 7 of 52 having evidence of widely metastatic cancer Ten patients had local disease 26 had regional metastases and six patients were in remission Three patients presented with neurologic symptoms coincident with recur- rence of a malignancy that had previously been in remission

Neurologic findings Patients presented with a characteristic pancerebellar disorder with truncal and limb ataxia dysarthria and nystagmus of subacute onset (1 day to 16 weeks) and subsequent stabilization Complete details of the neurologic

examination were available to us in 48 patients The ataxia was init ially asymmetric in 20 although in most ataxia became symmetric as the disease progressed Most patients were severely disabled by the neurologic syndrome with 37 of 48 patients being unable to walk or sit unassisted due to severe ataxia 9 of 48 could walk with some assistance and 2 of 48 could walk unassisted but were unsteady

All patients had some degree of horizontal nystagmus with a rotatory or vertical component in twenty-seven Seventeen patients were specifically reported to have downbeating nystagmus All of the 10 patients we examined had downbeating nystagmus we suspect that this finding was underre- ported in records we reviewed Five patients reported oscillopsia and 19 patients experienced diplopia However limitation of extraocular move- ments with unilateral or bilateral abducens palsies was detected in only six In 20 patients there was other bulbar involvement including dysphagia in 16 and facial weakness in seven Opsoclonus was reported in two patients and sleep myoclonus in one other

Signs or symptoms of involvement at other levels of the neuraxis were common but usually mild Although accurate mental status testing was diffi- cult t o confirm because of dysarthria and motor dysfunction 10 patients were believed clinically to have some cognitive impairment usually emotional lability and memory deficit Twenty-eight had extensor plantar responses or other long-tract signs Two patients had extrapyramidal rigidity and tremor or dyskinesias Twenty-six had hypore- flexia or mild distal sensory complaints suggesting peripheral neuropathy Two patients had progressive visual loss This finding was believed clinically to be a result of either optic neuropathy or retinal degeneration although this was unconfirmed by electrographic studies

Headache was an uncommon complaint prominent in only six patients Twenty patients com- plained of vertigo Nausea and vomiting were debil- itating symptoms in two

None of the patients was known t o have other immunologic rheumatic or collagen vascular dis- eases save for hypothyroidism in two patients and adult-onset diabetes mellitus in one

Laboratory eualuation CSF examination was performed in all patients Of the 42 patients in whom detailed CSF results were available only seven had normal CSF Thirty-five patients had inflammatory changes that included a predomi- nantly lymphocytic pleocytosis (between 6 and 93 WBCmm3) in 26 of 42 and elevated protein (between 48 and 106 mgdl) in 22 of 42 patients The ratio of CSF to serum IgG was increased in 12 of 14 patients for whom this information was available oligoclonal bands were present in 6 of 7 patients tested and elevated myelin basic protein reported in one

CT andor MRI was performed in all patients

Table 1 Clinical findings in 55 anti-Yo-positive PCD patients

Sex Women Men

26 to 85 years

Before diagnosis of cancer After diagnosis of cancer No cancer known

Severe (unable to walk) Moderate (walks with assist) Mild (walks but unsteady) Severity not known

Rotatory or vertical

EOM abnormality detected

Age

Time of neurologic presentation

Ataxia

Nystagmus

Dip 1 o p i a

Opsoclonus Myoclonus Dysphagia Facial weakness Cognitive impairment Long-tract signs Extrapyramidal signs Peripheral neuropathy Progressive visual loss Headache Vertigo Severe nausea and vomiting CSF

Negative cytology Normal Inflammatory Details not known

Negative for metastasis Cerebellar atrophy

Immunosuppressive therapy Plasmapheresis Steroids Cyclophosphamide Azathioprine ACTH

No response Mild transient improvement Mild sustained improvement

CT or MRI

Response to therapy

Living (291) Died

55 0

61 (median)

34 18 3

55 37 9 2 7

55 27 19 6 2 1

16 7

10 28 2

26 2 6

20 2

55 7

35 13

55 17 29 22 17 4 2 1

23 5 1

36 19

EOM Extraocular movement

Most of these studies were init ially normal although 17 patients had evidence of cerebellar atrophy on CT or MRI particularly later in the disease process In seven patients studied with 18F-flu- orodeoxyglucose positron emission tomography the mean regional metabolic rate for glucose was sig-


~~~~~~ ~ ~~ ~

Figure (A) Photomicrograph of normal cerebellar cortex from a 55-year-old man who died of disseminated carcinoma without neurologic involvement Purkinje cells are prominent at the junction of the molecular and granular layers (hematoxylin-eosin XlOO before 29 reduction) (B) View of the cerebellar cortex from a patient who died with anti- Yo-positive PCD demonstrating total Purkinje cell loss Note the absence of inflammatory infiltrates (hematoxylin-eosin XlOO before 29 reduction)

nificantly reduced in the cerebellum and several cortical regions as well when compared with that of normal indi~idua1sl~

Treatment On the rationale that this neurologic syndrome was autoimmune several immunosuppressive therapies were tried in various combi- nations in a total of 29 patients These included plasmapheresis i n 22 pat ients (a t least five exchanges) There was mild but transient improvement in the symptoms of ataxia and dysarthria in four patients Another patient had a moderate sustained benefit regaining her ability to walk with assistance This correlated with a decrease in her serum antibody titers from 14000 pre-treatment t o 1200 post-treatment However five other patients with documented decline in serum antibody titers after treatment showed no clinical response possibly related to the finding that there was no corresponding decline in CSF antibody titers16 High-dose steroids (40 to 100 mgd for at least 2 weeks) gave mild but transient improvement in one of 17 patients treated There was no beneficial effect of cyclophosphamide in four patients azathioprine in two o r ACTH in one patient One patient was reported t o have had moderate improvement with treatment of the underlying tumor

At the time of most recent follow-up 36 patients are still living up to 77 months after the onset of neurologic symptoms Most of these are in remission from their malignancies but remain severely disabled neurologically Nineteen patients have died between 2 and 36 months after the onset of their neurologic symptoms due to progression of their oncologic disease and inanition (table 1)

Pathology The neuropathologic findings at


autopsy were available for review in three cases and conformed to previous descriptions of PCD in patients with breast and gynecologic ~ a n c e r ~ All were characterized chiefly by cerebellar cortical atrophy with near-total depletion of Purkinje cells and proliferation of Bergmann astrocytes (figure) Thinning of the granule cell population was an additional feature of two cases Scattered small lymphocytes mainly T-cells by immunotyping were noted in the cerebellar leptomeninges but in no case were inflammatory infiltrates identified in the cerebellar cortex proper Small numbers of mature lymphocytes again mainly T-cells also cuffed blood vessels in the dentate nucleus but were not associated with appreciable neuronal loss As expected the dentate amiculum (composed nor- mally of Purkinje cell axons) exhibited axonal depopulation and secondary demyelination in all cases

Microscopic sections of the PCD-associated neoplasm at its primary site were available for review in seven cases (one fallopian tube one endometrial two mammary and three ovarian) Both breast pri- maries were high-grade poorly differentiated infil- t r a t ing adenocarcinomas of the duct type Similarly the endometrial ovarian and tuba1 neoplasms were found to be high-grade mullerian adenocarcinomas composed of solid and papillary ele- ments An unusual and striking feature common to the stroma of all seven neoplasms was a conspicu- ous lymphoid infiltrate dominated by mature plasma cells As previously described12 expression of the Yo antigen by PCD-associated neoplasms was demonstrable in immunohistochemical and Western blot assay in all 10 instances in which fresh tumor tissue was available for analysis

Table 2 Autoantibodies in paraneoplastic cerebellar degeneration

Antigen distribution titer (immunohistochemistry)

Immunoblots (antigen Mr) Author Tumor (no)

Hodgkinrsquos ( 1 ) Trotter et a120 1976

Stefansson et ally 1981

Brown et alZ2 1985

Purkinje cell cytoplasm 120

Axons dendrites in cerebral cerebellar cortex

Purkinje cell cytoplasm neurons in deep cerebellar nuclei brainstem forebrain

Purkinje cell cytoplasm

Hodgkinrsquos (1)

Lung (small cell) (1) 85 Mouse cerebellum brain spinal cord

210 Kornguth et aP3 1985

Rodriguez et aP4 1986

Tanaka et aP6 1986

Ovary (1)

ldquoGynecologic cancerrdquo (4) Purkinje cell cytoplasm

Non-Hodgkinrsquos (1) Purkinje cell cytoplasm 250 125 (cerebrum) 125 (cerebellum) Rat cytoplasmic proteins

- Greenlee and BrasheaP 1983

Greenlee et aP1986 Greenlee and Liptonz8 1986

Jaeckle e t a18 1985


Purkinje and granule cell cytoplasm Purkinje and granule cell nuclei CNS neurons 1320


Ovary breast (9)

Lung (small cell) (3) Breast (1)

34-38 62-64 Human Purkinje cell

Ovary breast (7)

Cunningham et alg 1986

Bourdette and N i I a ~ e r ~ ~ 1987

Royal et a130 1987

Anderson et al3I 1988

Lung (small cell) (5) Hodgkinrsquos (5)

Benign monoclonal gammopathy

Breast (1)

Absent Absent


Purkinje cell cytoplasm 34-38 62-64

5664 68 80 Purkinje cell cytoplasm fine granular pattern human rat rabbit bovine 13000

Weak staining cortical hippocampal brainstem neurons 1 5 0


Lung (adeno) (1)

Ovary (9) breast (61 adenocarcinoma

unknown 1rdquo (3) Lung (adeno) (l) colon (1) Lung (small cell) (1) Breast (1)

34-38 62-64

-

35-40 (anti-Hu) 53-61 79-84

5258

3046 3840

Anderson et a17 1988


All neuronal nuclei All neuronal nuclei

Ovary (21 uterus (2)

Purkinje stellate basket cells deep cerebellar nuclei cortical hippocampal neurons 110000 All neuronal cells 1100000

Tsukamoto et a P 1989

Breast ( l ) lung (1)


Discussion This report confirms and extends findings previously reported on 18 patients from this laboratory7 and in a similar survey of 32 PCD patients published recently from the Mayo Clinic In the Mayo series 16 antibody-positive patients were identified17 From these reports emerges a rather stereotypic picture of the anti-Yo antibody- positive PCD patient Always female and usually not previously known to have cancer she develops over a matter of weeks a severe pancerebellar disorder with t runcal and appendicular a taxia dysarthria and nystagmus often with a downbeating component The clinical findings stabilize within a couple of months leaving most patients unable to walk without the assistance of one or two people unable to write legibly frequently unable to read or watch television because of oscillopsia or diplopia and having difficulty in being understood when speaking The behavioral and long-tract signs when present are usually mild and opsoclonus and myoclonus are not characteristic features Interestingly two of our patients had progressive prechiasmal visual loss possibly due to optic neuropathy or retinal degeneration Most patients remain stable but severely disabled and except in a few isolated cases18 do not improve with plasmapheresis or immunosuppression With few excep- tions the anti-Yo antibody-positive PCD patient is eventually found to have an associated gynecologic cancer

Several different autoantibodies have been identified in patients with PCD (table 2) In comparison with anti-Yo-positive PCD patients those without the anti-Yo antibody though pathologically similar are frequently clinically distinct and make up a heterogeneous group Taken together patients without the anti-Yo antibody have an approximately equal sex distribution a variety of associated malignancies (most commonly bronchial carcinoma and Hodgkinrsquos lymphoma) and more frequently present with their neurologic syndrome after the malignancy has been diagnosed Particular subsets of patients with PCD are discussed in the following two papers and e l s e ~ h e r e ~ - ~ J ~ J ~ ~ ~ ~

With the data reported here and with other recently reported cases or series of PCD it seems likely that PCD is a group of disorders each related to a particular cancer or cancers The utility of dif- ferentiating between the different anti-Purkinje cell antibodies is that when a particular antibody is present such as anti-Yo it strongly suggests the presence of an underlying neoplasm and directs the search for the occult malignancy to one or a few organs We believe that the presence of the anti-Yo antibody warran ts a n aggressive diagnostic approach that begins with careful breast and pelvic examination mammography pelvic CT and mea- surement of ovarian tumor antigen CA 125 If no malignancy is revealed with this initial workup repeat mammography pelvic examination under anesthesia and uterine D amp C should be performed If there is still no cancer evident surgical


exploration and removal of pelvic organs may be warranted particularly in the postmenopausal woman

Unfortunately early detection and even cure of the underlying cancer does not usually affect the neurologic symptoms Although there are occasion- al reports of patients with paraneoplastic syndromes responding to treatment of the underlying tumor21 none of the patients in this series substantially improved after successful treatment of the cancer and follow-up of more than 4 years In none of the patients has there been progression of the cerebellar dysfunction after treatment of the cancer however in most of the patients the cerebellar dysfunction had stabilized by the time the cancer diagnosis was made and treatment instituted Interestingly the anti-Yo antibody has persisted in all the patients we have followed after what is assumed to be successful treatment of the cancer In two patients in remission for more than 4 years the antibody persists in the serum although there has been no progression of their cerebellar dysfunction or evidence of recurrent tumor Thus the major importance of identification of the anti-Yo antibody is that early diagnosis leads to treatment and at times cure of the cancer Identification of the antibody does not appear to be helpful in ame- liorating the neurologic disease

The pathogenesis of anti-Yo-positive PCD is unknown The high titer of antibody suggests an autoimmune mechanism but there are no reports of successful attempts to reproduce the disease in experimental animals A recent report of intrathe- cal injection of anti-Yo antibodies into experimental animals was apparently successful in getting the antibody to the Purkinje cells but not in caus- ing neurologic dy~funct ion~~ Furthermore autopsy studies indicate that in most patients there is no inflammation around the degenerated Purkinje cells Thus there is no direct evidence for either a humoral- o r cell-mediated immune reaction in patients with anti-Yo-positive PCD Further work will be necessary to establish the pathogenesis of the disorder

References 1

2

3

4

5

6

Brain WR Daniel PM Greenfield JG Subacute cortical cerebellar degeneration and its relation t o carcinoma J Neurol Neurosurg Psychiatry 19511459-75 Brain WR Wilkinson M Subacute cerebellar degeneration associated with neoplasms Brain 196588465-478 Henson RA Urich H eds Cancer and the nervous system the neurological manifestations of systemic disease Oxford UK Blackwell Scientific 1982346-367 Hammack JE Posner JB Paraneoplastic cerebellar degeneration In Plaitakis A ed Cerebellar degenerations clinical neurobiology Boston Kluwer Academic 1992 Anderson NE Rosenblum MK Graus F Wiley RG Posner JB Autoantibodies in paraneoplastic syndromes associated with small-cell lung cancer Neurology 1988381391-1398 Dalmau J Graus F Rosenblum MK Posner JB Anti-Hu associated paraneoplastic encephalomyelitissensory neu- ronopathy a clinical s tudy of 7 1 pa t ien ts Medicine 19927159-72

7 Anderson NE Rosenblum MK Posner JB Paraneoplastic cerebellar degeneration clinical-immunological correlations Ann Neurol 198824559-567

8 Jaeckle KA Graus F Houghton A Cardon-Cardo C Nielsen SL Posner JB Autoimmune response of patients with paraneoplastic cerebellar degeneration t o a Purkinje cell cytoplasmic protein antigen Ann Neurol 198518592-600

9 Cunningham J Graus F Anderson N Posner JB Partial characterization of the Purkinje cell antigens in paraneoplastic cerebellar degeneration Neurology 1986361163- 1168

10 Dropcho EJ Chen Y Posner JB Old LJ Cloning of a brain protein identified by autoantibodies from a patient with paraneoplastic cerebellar degeneration Proc Natl Acad Sci

11 Furneaux HM Dropcho E J Barbut D e t al Characterization of a cDNA encoding a 34-kDa Purkinje neuron protein recognized by sera from patients with paraneoplastic cerebellar degeneration Proc Natl Acad Sci USA

12 Furneaux HM Rosenblum MK Dalmau J Wong E Woodruff P Posner JB Selective expression of Purkinje cell antigens in tumor tissue derived from patients with paraneoplastic cerebellar degenerat ion N Engl J Med

13 Chen Y Rettig WJ Yenamandra AK e t a] Cerebellar degeneration-related (CDR) antigen a highly conserved neu- roectodermal marker mapped to chromosome X in human and mouse Proc Natl Acad Sci USA 1990873077-3081

14 Fathallah-Shaykh H Wolf S Wong E Posner JB Furneaux HM Cloning of a leucine zipper protein recognized by the sera of patients with antibody-associated paraneoplastic cerebellar degenerat ion Proc N a t l Acad Sci USA

15 Anderson NE Posner JB Sidtis J J e t al The metabolic anatomy of paraneoplastic cerebellar degeneration Ann Neurol 198823533-540

16 Gram F Abos J Roquer J Mazzara R Pereira A Effect of plasmapheresis on serum and CSF autoantibody levels in CNS paraneoplastic syndromes Neurology 1990401621- 1623

17 Hammack J E Kimmel DW OrsquoNeill BP Lennon VA Paraneoplastic cerebellar degeneration a clinical comparison of patients with and without Purkinje cell cytoplasmic antibodies Mayo Clin Proc 1990651423-1431

18 Cocconi G Ceci G Jinvarra G et al Successful treatment of subacute cerebellar degeneration in ovarian carcinoma with plasmapheresis a case report Cancer 1985562318-2320

19 Stefansson K Ante1 JP Wollman RL Levin KH Larson R Arnason BGW Anti-neuronal antibodies in serum of a pat ient with Hodgkinrsquos disease and cerebellar a taxia [abstract] Neurology 198131(No 4 Pt 2)126

USA 1987844552-4556

1989862873-2877

19903221844-1851

1991883451-3454

20 Trotter JL Hendin BA Osterland CK Cerebellar degeneration with Hodgkinrsquos disease an immunological study Arch Neurol 197633660-661

21 Kearsley JH Johnson P Halmagyi GM Paraneoplastic cerebellar disease remission with excision of the primary tumor Arch Neurol 1985421208-1210

22 Brown RH J r Ronthal M Come S et al Antibodies t o 85000 dalton protein in paracarcinomatous cerebellar degeneration [abstract] Neurology 198535(suppl 1)288

23 Kornguth S Kalinke T Grunwald G Brooks B Zimmerman E Anti-neurofilament antibodies associated with paraneoplastic syndromes [abstract] Fed Proc 198544966

24 Rodriguez M Truh LI OrsquoNeill BP Lennon VA Autoimmune paraneoplastic cerebellar degeneration ultrastructural localization of antibody-binding sites in Purkinje cells Neurology 1988381380-1386

25 Tanaka K Yamazaki M Sat0 S Toyoshima I Yamamoto A Miyatake T Antibodies to brain proteins in paraneoplastic cerebellar degeneration Neurology 1986361169-1172

26 Greenlee J E Brashear HR Antibodies to cerebellar Purkinje cells in patients with paraneoplastic cerebellar degenerat ion a n d ovarian carcinoma Ann Neurol

27 Greenlee J E Brashear HR Jaeckle KA Stroop WG Anticerebellar antibodies in sera of patients with paraneoplastic cerebellar degeneration studies of antibody specifici- ty and response to plasmapheresis [abstract] Ann Neurol 198620 139

28 Greenlee JE Lipton HL Anticerebellar antibodies in serum and cerebrospinal fluid of a patient with oat cell carcinoma of the lung and paraneoplastic cerebellar degeneration Ann Neurol 19861982-85

29 Bourdette DN Nilaver G Cerebellar degeneration associated with anti-Purkinje cell antibodies and benign IgG monoclonal gammopathies [abstract] Neurology 198737(suppl 1)291

30 Royal W 111 Galasko DR McKhann GM Cunningham JM Dropcho EJ Clinical course immunologic and biochemical features of a patient with paraneoplastic cerebellar dysfunction [abstract] Neurology 198737(suppl 1)305-306

31 Anderson NE Budde-Steffen C Wiley RG et al A variant of the anti-Purkinje cell antibody in a patient with paraneoplastic cerebellar degeneration Neurology 1988381018- 1026

32 Tsukamoto T Yamamoto H Iwasaki Y Yoshie 0 Terunuma H Suzuki H Antineural autoantibodies in patients with paraneoplastic cerebellar degeneration Arch Neurol

33 Gram F Illa I Agusti M Ribalta T Cruz-Sanchez F Juarez C Effect of intraventricular injection of an anti-Purkinje cell antibody (anti-Yo) in a guinea pig model J Neurol Sci

198314609-613

1989461225-1229

199110682-87


DOI 101212WNL421019311992421931 Neurology

K Peterson MD M K Rosenblum H Kotanides MS et al positive patientsminus

Yo antibodyminusParaneoplastic cerebellar degeneration IA clinical analysis of 55 anti

This information is current as of October 1 1992

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Inc All rights reserved Print ISSN 0028-3878 Online ISSN 1526-632Xsince 1951 it is now a weekly with 48 issues per year Copyright copy 1992 by Edgell Communications

reg is the official journal of the American Academy of Neurology Published continuouslyNeurology

ined by one or more of the authors referring physicians sending sera andlor CSF for antibody testing provided the neurologic and oncologic profiles Telephone calls to the physicians most recently caring for the patients provided follow-up as of December 1991 Microscopic slides and blocks of the cerebellum obtained at autopsy in three patients and tumor tissue in seven patients were studied directly by us

Serum and CSF database Approximately 2000 sera andor CSF samples have been examined in our laboratory for the presence of anticerebellar antibodies These samples were sent from throughout the United States and many other countries by physicians suspecting the diagnosis of a neurologic paraneoplastic syndrome Some patients had known cancers whereas others did not All samples were s tudied by immunofluorescence or immunoperoxidase histochemistry and by Western blotting against Purkinje cell extracts A search of the data- bank also identified all patients in 1989 and 1990 with cerebellar syndromes with or without cancer and all patients with ovarian or breast cancer with or without cerebellar syndromes

Immunologic techniques Immunohistochemistry and Western blott ing techniques against Purkinje cell extracts as well as the CDR 62 fusion protein that corre- sponds to the 62 kd antigen to which the anti-Yo antibody binds have been described extensively in previous publications from this l a b ~ r a t o r y ~ - ~

Results Immunologic findings Serum or CSF from 55 patients was positive for the anti-Yo antibody as determined by immunohistochemistry and Western blotting In 41 of 41 patients tested sera also reacted positively against the Yo fusion pro- tein14

Several patients who had atypical histochemical staining andor atypical immunoblotting were excluded Excluded patients included one whose serum was positive by histochemistry but reacted on Western blotting against Purkinje cell extracts with a band of 68 kd (but not 34 kd ) and was negative against the Yo fusion protein Three patients had atypical Purkinje cell cytoplasmic staining and were negative on immunoblotting Two patients with PCD showed neuronal nuclear staining and a band at 35 to 40 kd on Western blot (typical of the anti-Hu antibody) but were negative when tested against the Yo fusion protein and one other with atypical nuclear staining was negative with both immunoblotting techniques

Thirteen patients with Hodgkins disease and PCD 45 patients with breast cancer and 24 with ovarian cancer with or without cerebellar syndromes 325 patients with cerebellar syndromes with or without cancer and 50 normal controls (blood bank donors) were also negative by both histochemistry and immunoblotting

Clinical results The 55 patients with the typical anti-Yo antibody presented a stereotypic clinical syndrome All patients were women 26 to 85 years old

Tumors Fifty-two of the patients currently have histologically proven malignancies The most common tumor ovarian was found in 26 of 55 patients


13 had breast cancer and seven had other gynecologic malignancies (four endometrial two fallopian tube and one mesovarium) One patient had both breast and fallopian tube cancers One patient had an adenocarcinoma of the lung and is without known gynecologic malignancy

There were six patients with adenocarcinoma of unknown primary Three of these presented with axillary nodes likely representing breast cancer although no primary was found in the breast One patient with adenocarcinoma of unknown primary had had resection 2 years previously of an ovarian mass that had shown benign pathology at autopsy this patient was found to have had a periaortic node pathologically suggestive of ovarian cancer and had staining for CA 125 antigen which is associated with ovarian cancers One patient presented with carcinoma in an inguinal lymph node One other patient had a poorly differentiated adenocarcinoma in an abdominal lymph node compatible with ovarian cancer but no ovarian tumor was found At autopsy 3 years later she was found to have a hepatoma but no adenocarcinoma the origi- nal primary was not found

Three patients had no tumor identified One of these patients had resection of an ovarian mass with benign histology (ovarian cystadenoma) she died 24 months after the onset of her neurologic syndrome and no cancer was found at autopsy Two patients are still living up to 24 months after the onset of their neurologic disorder and have so far shown no evidence of malignancy despite serial physical and radiologic examinations

In 34 of 52 patients with known cancer the neurologic syndrome preceded the diagnosis of malignancy by up to 15 months and in many of the cases prompted a search for the underlying cancer Of these 34 patients 16 had ovarian cancer notably four had microscopic disease not found by routine diagnostic testing and detected only at laparotomy However one patient with a negative mammogram and normal pelvic examination underwent laparoscopy with ovarian biopsy and then hys- terectomy and bilateral salpingo-oophorectomy without a malignancy being found Four months after the initial normal mammogram a breast abnormality was detected and biopsy revealed an intraductal carcinoma

Most patients with known cancer had limited oncologic disease at the time of onset of neurologic symptoms with only 7 of 52 having evidence of widely metastatic cancer Ten patients had local disease 26 had regional metastases and six patients were in remission Three patients presented with neurologic symptoms coincident with recur- rence of a malignancy that had previously been in remission

Neurologic findings Patients presented with a characteristic pancerebellar disorder with truncal and limb ataxia dysarthria and nystagmus of subacute onset (1 day to 16 weeks) and subsequent stabilization Complete details of the neurologic









Sex Women Men

26 to 85 years





Age


Ataxia

Nystagmus

Dip 1 o p i a






CT or MRI

Response to therapy

Living (291) Died

55 0

61 (median)

34 18 3

55 37 9 2 7

55 27 19 6 2 1

16 7

10 28 2

26 2 6

20 2

55 7

35 13

55 17 29 22 17 4 2 1

23 5 1

36 19




~~~~~~ ~ ~~ ~














Brown et alZ2 1985





Hodgkinrsquos (1)




Tanaka et aP6 1986

Ovary (1)









Ovary breast (9)



Ovary breast (7)



Royal et a130 1987




Breast (1)

Absent Absent






Lung (adeno) (1)



34-38 62-64

-

35-40 (anti-Hu) 53-61 79-84

5258

3046 3840
















References 1

2

3

4

5

6















USA 1987844552-4556

1989862873-2877

19903221844-1851

1991883451-3454















198314609-613

1989461225-1229

199110682-87












Reprints












Sex Women Men

26 to 85 years





Age


Ataxia

Nystagmus

Dip 1 o p i a






CT or MRI

Response to therapy

Living (291) Died

55 0

61 (median)

34 18 3

55 37 9 2 7

55 27 19 6 2 1

16 7

10 28 2

26 2 6

20 2

55 7

35 13

55 17 29 22 17 4 2 1

23 5 1

36 19




~~~~~~ ~ ~~ ~














Brown et alZ2 1985





Hodgkinrsquos (1)




Tanaka et aP6 1986

Ovary (1)









Ovary breast (9)



Ovary breast (7)



Royal et a130 1987




Breast (1)

Absent Absent






Lung (adeno) (1)



34-38 62-64

-

35-40 (anti-Hu) 53-61 79-84

5258

3046 3840
















References 1

2

3

4

5

6















USA 1987844552-4556

1989862873-2877

19903221844-1851

1991883451-3454















198314609-613

1989461225-1229

199110682-87












Reprints




~~~~~~ ~ ~~ ~














Brown et alZ2 1985





Hodgkinrsquos (1)




Tanaka et aP6 1986

Ovary (1)









Ovary breast (9)



Ovary breast (7)



Royal et a130 1987




Breast (1)

Absent Absent






Lung (adeno) (1)



34-38 62-64

-

35-40 (anti-Hu) 53-61 79-84

5258

3046 3840
















References 1

2

3

4

5

6















USA 1987844552-4556

1989862873-2877

19903221844-1851

1991883451-3454















198314609-613

1989461225-1229

199110682-87












Reprints









Brown et alZ2 1985





Hodgkinrsquos (1)




Tanaka et aP6 1986

Ovary (1)









Ovary breast (9)



Ovary breast (7)



Royal et a130 1987




Breast (1)

Absent Absent






Lung (adeno) (1)



34-38 62-64

-

35-40 (anti-Hu) 53-61 79-84

5258

3046 3840
















References 1

2

3

4

5

6















USA 1987844552-4556

1989862873-2877

19903221844-1851

1991883451-3454















198314609-613

1989461225-1229

199110682-87












Reprints











References 1

2

3

4

5

6















USA 1987844552-4556

1989862873-2877

19903221844-1851

1991883451-3454















198314609-613

1989461225-1229

199110682-87












Reprints

















USA 1987844552-4556

1989862873-2877

19903221844-1851

1991883451-3454















198314609-613

1989461225-1229

199110682-87












Reprints














Reprints




Paraneoplastic cerebellar degeneration. -...

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